Article
Nutrition & Dietetics
Akira Takahashi
Summary: This study investigates the effectiveness of combined use of the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) and zinc supplementation in stabilizing serum copper and zinc concentrations in patients undergoing hemodialysis. The results suggest that zinc supplementation significantly increases serum zinc concentrations, while roxadustat treatment significantly increases serum copper concentrations. However, when zinc supplementation is initiated or increased in patients treated with roxadustat, copper and zinc concentrations are normalized.
Article
Urology & Nephrology
Zhikai Yang, Tiantian Ma, Xiao Xu, Gang Fu, Jing Zhao, Ying Xu, Bin Yang, Di Song, Sainan Zhu, Jicheng Lv, Jie Dong
Summary: This study aimed to compare the efficacy of a lower starting dose of roxadustat with the standard dose among PD patients. The results showed no difference in achieving the Hb target between the low-dose and standard-dose groups. Both groups showed significant improvement in Hb levels.
KIDNEY INTERNATIONAL REPORTS
(2022)
Article
Urology & Nephrology
Atsuyuki Tokuyama, Hiroyuki Kadoya, Atsushi Obata, Takahiro Obata, Tamaki Sasaki, Naoki Kashihara
Summary: This study found that in CKD patients, switching from darbepoetin alfa to roxadustat may lead to abnormal levels of thyroid-stimulating hormone in hemodialysis patients, which can be reversed after stopping the medication.
CLINICAL KIDNEY JOURNAL
(2021)
Review
Pharmacology & Pharmacy
David Czock, Frieder Keller
Summary: The pharmacokinetics of roxadustat in healthy volunteers show well-characterized distribution volume, clearance rates, and bioavailability, with a strong impact on erythropoietin (EPO) and hemoglobin (ΔHb) levels that can be modeled through sigmoidal Hill equations.
CLINICAL PHARMACOKINETICS
(2022)
Article
Pharmacology & Pharmacy
Anthony Markham
Summary: Enarodustat, an orally active HIF-PH inhibitor, is being developed as an alternative to injectable erythropoiesis-stimulating agents for the treatment of anemia associated with CKD. Approved in Japan, the drug is currently undergoing clinical development in the USA and South Korea. This article outlines the key milestones in the development of enarodustat leading to its first approval for CKD-associated anemia.
Article
Pediatrics
Yan Yang, Yan Chen, Yang Yang, Haitao Bai, Bizi He, Dengli Liu
Summary: This case report suggests that roxadustat may be a useful treatment option for refractory renal anemia in children. However, further prospective clinical trials are needed to confirm its efficacy and safety.
PEDIATRIC NEPHROLOGY
(2023)
Article
Pharmacology & Pharmacy
Sohita Dhillon
Summary: Desidustat, an orally available small molecule inhibitor, is developed for the treatment of anaemia associated with chronic kidney disease, COVID-2019 infections, and chemotherapy-induced anaemia. It stimulates erythropoiesis by inhibiting prolyl hydroxylase enzymes. Desidustat has received its first approval in India and is undergoing clinical development in other countries.
Review
Pharmacology & Pharmacy
Mai Sugahara, Tetsuhiro Tanaka, Masaomi Nangaku
Summary: For the past 3 decades, erythropoiesis-stimulating agents (ESA) in conjunction with iron supplementation has been the mainstay of treatment for anemia in chronic kidney disease (CKD). However, recent studies have raised concerns about the cardiovascular risks associated with high hemoglobin (Hb) targets. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as novel agents that stimulate endogenous erythropoietin production and induce erythropoiesis in CKD patients. While HIF-PHIs have shown noninferiority to ESA in clinical trials, there are still concerns about their long-term safety and potential risks.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Pharmacology & Pharmacy
Yasunobu Kouki, Naoto Okada, Kosuke Saga, Masakazu Ozaki, Atsuyuki Saisyo, Takashi Kitahara
Summary: HIF-PHI is a novel treatment for renal anemia that increases erythropoietin production but may also lead to hypothyroidism. This study used the Japanese Adverse Drug Event Report database to analyze the clinical impact of HIF-PHIs on thyroid function and found a disproportional signal for hypothyroidism with roxadustat. Monitoring of thyroid function should be conducted during roxadustat administration.
JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Xuejie Zhang, Ruoyu Jia, Zhifang Zheng, Luhua Jiang, Yizhou Xu, Ashok Raj, Dong Sun
Summary: Compared with ESAs, roxadustat significantly decreased hepcidin level, attenuated the increase in serum soluble transferrin receptor level, and reduced the proportion of patients with functional iron deficiency in PD patients.
EUROPEAN JOURNAL OF MEDICAL RESEARCH
(2023)
Article
Hematology
John Glaspy, Nashat Y. Gabrail, Patricia Locantore-Ford, Tyson Lee, Katharina Modelska, Vivek Samal, David H. Henry
Summary: Roxadustat, a VEGF receptor modulator, is effective and safe for chemotherapy-induced anemia in cancer patients.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Urology & Nephrology
Xiaoshuang Wang, Hezhou Cai, Haifan Xu, Liqun Chen
Summary: The study aimed to investigate the efficacy of roxadustat in treating EPO hypo-responsive anemia in hemodialysis patients. The results showed that roxadustat effectively improved anemia, and the platelet-to-lymphocyte ratio and duration of dialysis were independent predictors of roxadustat efficacy.
CLINICAL NEPHROLOGY
(2023)
Review
Pharmacology & Pharmacy
Limei Xiong, Hui Zhang, Yannan Guo, Yue Song, Yuhong Tao
Summary: Vadadustat appears to be a safe and effective treatment for anemia in CKD patients, improving Hb levels and promoting iron utilization. Compared to placebo, it significantly reduces levels of hepcidin and ferritin and increases iron-binding capacity. However, compared to placebo or darbepoetin alfa, it may increase the risk of nausea and diarrhea.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Transplantation
Masaomi Nangaku, Kazuoki Kondo, Kiichiro Ueta, Yoshimasa Kokado, Genki Kaneko, Hiroki Matsuda, Yutaka Kawaguchi, Yasuhiro Komatsu
Summary: The study compared the efficacy and safety of vadadustat with darbepoetin alfa in Japanese anemic patients on hemodialysis. Vadadustat was found to be noninferior to darbepoetin alfa in maintaining hemoglobin levels within the target range, with similar adverse events observed in both groups. This suggests that vadadustat can be a viable alternative to ESA in managing anemia in Japanese hemodialysis patients.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2021)
Article
Transplantation
Masaomi Nangaku, Youssef M. K. Farag, Emil DeGoma, Wenli Luo, Dennis Vargo, Zeeshan Khawaja
Summary: The results of the studies support the development of vadadustat for the treatment of anemia in patients with CKD, showing significant efficacy in increasing Hb levels and adjusting iron utilization and mobilization. The incidence of adverse events during the primary efficacy period was similar to or slightly higher than the placebo group, with common events including nausea, hypertension, diarrhea, and nasopharyngitis.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2021)
Article
Chemistry, Medicinal
Zhihong Li, Qidong You, Xiaojin Zhang
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Xiaojin Zhang, Yonghua Lei, Tianhan Hu, Yue Wu, Zhihong Li, Zhensheng Jiang, Changyong Yang, Lianshan Zhang, Qidong You
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Review
Chemistry, Medicinal
Qijie Gong, Jiabao Hu, Pengfei Wang, Xiang Li, Xiaojin Zhang
Summary: Beta-Lapachone, a natural product from South America, has diverse pharmacological activities and its derivatives are studied for enhanced potency and overcoming limitations.Clinical trials related to beta-lap and its derivatives are summarized.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Pengfei Wang, Qijie Gong, Jiabao Hu, Xiang Li, Xiaojin Zhang
Summary: The study focuses on the role of reactive oxygen species in various diseases and the development of drugs for the targeted treatment and precise diagnosis of ROS-related diseases, also discussed are the activation mechanisms of ROS-responsive prodrugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Yancheng Yu, Quanwei Yu, Simeng Liu, Chenyang Wu, Xiaojin Zhang
Summary: This study involves the identification and evaluation of HIF-2 agonists, M1001 and its analog M1002, highlighting their potential as novel therapeutic agents for human oxygen metabolism. The use of molecular dynamics simulations allowed for the proposal of a plausible binding mode for these agonists, complemented by the synthesis and evaluation of compounds to verify the proposed mode. Compound 10 demonstrated improved agonistic activity and reduced toxicity compared to M1002, indicating its potential for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Yue Wu, Zhihong Li, Michael A. McDonough, Christopher J. Schofield, Xiaojin Zhang
Summary: FIH is a crucial factor in regulating HIF activity by hydroxylation of specific asparagines. Inhibitors of FIH, though less studied, show potential in altering metabolism and therapeutic applications.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Qijie Gong, Fulai Yang, Jiabao Hu, Tian Li, Pengfei Wang, Xiang Li, Xiaojin Zhang
Summary: NQO1 is overexpressed in many cancer cells, making it a potential biomarker for cancer diagnosis and targeted therapy. A naphthoquinone trigger group designed based on the analysis of NQO1 catalytic pocket showed significantly increased sensitivity to NQO1. Probe A, based on the naphthoquinone trigger group, exhibited eight times higher sensitivity to NQO1 in vivo compared to probe B based on the benzoquinone trigger group.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Qijie Gong, Quanwei Yu, Nan Wang, Jiabao Hu, Pengfei Wang, Fulai Yang, Tian Li, Qidong You, Xiang Li, Xiaojin Zhang
Summary: In this study, a series of novel NQO1 substrates were designed by introducing aliphatic nitrogen-containing side chains to form cation-pi interactions with the L-shaped pocket of NQO1. Compound 4 was identified as the most efficient substrate for NQO1, with high reduction rate and catalytic efficiency, as well as increased water solubility. Compound 4 showed potent antitumor activity against NQO1-rich cancer cells through ROS generation, highlighting the potential of cation-pi interactions for developing promising NQO1-targeting antitumor candidates with improved druglike properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Yancheng Yu, Fulai Yang, Quanwei Yu, Simeng Liu, Chenyang Wu, Kaijun Su, Le Yang, Xiaoqian Bao, Zhihong Li, Xiang Li, Xiaojin Zhang
Summary: A novel HIF-2 alpha agonist, compound 26, was discovered with potent nanomolar activity and the ability to enhance HIF-2 dimerization. It showed good pharmacokinetic and in vivo safety profiles, and when combined with the prolyl hydroxylase inhibitor AKB-6548, it synergistically increased plasma erythropoietin levels in mice and alleviated zebrafish anemia induced by doxorubicin. These findings suggest potential therapeutic implications for HIF-2 alpha agonists in the treatment of renal anemia.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Kaijun Su, Zhihong Li, Linjian Zhang, Shaocong Fang, Mingxuan Mao, Zhuoli Sun, Xiaojin Zhang
Summary: This study developed a novel type of PHD2 inhibitor, with compound 25 showing potent inhibition of PHD2 in vivo and no obvious toxicity, making it a promising candidate for the treatment of renal anemia.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Zhihong Li, Yue Wu, Shuai Zhen, Kaijun Su, Linjian Zhang, Fulai Yang, Michael A. McDonough, Christopher J. Schofield, Xiaojin Zhang
Summary: Target-directed dynamic combinatorial chemistry is an important tool in drug discovery, but faces challenges in analyzing complex mixtures. In this study, we propose a simple alternative called in situ inhibitor synthesis and screening (ISISS), which combines high-throughput bioorthogonal synthesis with screening for target binding using fluorescence. We demonstrate the effectiveness of the ISISS method in discovering a potent acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with comparable in vivo potency to an approved medicine.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Zhihong Li, Shuai Zhen, Kaijun Su, Anthony Tumber, Quanwei Yu, Ying Dong, Michael McDonough, Christopher J. Schofield, Xiaojin Zhang
CHEMICAL COMMUNICATIONS
(2020)
Review
Pharmacology & Pharmacy
Karlie R. Sharma, Christine M. Colvis, Griffih P. Rodgers, Douglas M. Sheeley
Summary: There are many genes within the druggable genome that have not been studied, and the US National Institutes of Health's program provides resources to explore these genes, with the potential for rapid impact on human health.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Mohammad Sameer Khan, B. H. Jaswanth Gowda, Waleed H. Almalki, Tanuja Singh, Amirhossein Sahebkar, Prashant Kesharwani
Summary: Mitochondria-specific functional liposomes hold great potential for cancer therapy. This review discusses the association between mitochondria and tumor formation, as well as the advantages of liposomes in delivering drugs to mitochondria.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Choong Yong Ung, Cristina Correia, Hu Li, Christopher M. Adams, Jennifer J. Westendorf, Shizhen Zhu
Summary: With increasing human life expectancy, the global medical burden of chronic diseases is growing. Chronic diseases often involve malfunctioning of multiple organs, and understanding the interorgan crosstalk is crucial to understanding the etiology of chronic diseases. Researchers have proposed the locked-state model (LoSM) and cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. The findings have important clinical implications for improving treatments for chronic diseases.
DRUG DISCOVERY TODAY
(2024)
